The long-term goal of our research is to develop a novel treatment for osteoporosis that will stimulate bone formation. An estimated 10 million Americans over the age of 50 have osteoporosis, and another 34 million people are at high risk of developing this disease. One out of every two women and one in four men over 50 will have an osteoporosis-related fracture in their lifetime. Osteoporosis is responsible for more than 1.5 million fractures annually, including 300,000 hip fractures, approximately 700,000 vertebral fractures, 250,000 wrist fractures, and more than 300,000 fractures at other sites. Nationally, the estimated direct expenditures for osteoporosis and related fractures are $14 billion per year. Post-menopausal osteoporosis is characterized by an increased rate of bone remodeling;however, bone formation does not keep pace with increased bone resorption resulting in net loss of bone. Most current treatments for osteoporosis are directed at inhibiting increased bone resorption, and the only clinically available anabolic agent (PTH) is administered by injection and can only be used for 24 months. A key event in the development of post-menopausal osteoporosis is an increase in the levels of pro-inflammatory cytokines such as TNF and IL-1. These cytokines drive the production and activation of the bone resorptive cells and this process has been the focus of intensive research efforts. However, these cytokines have also been shown to inhibit bone formation, and this phenomenon is likely responsible for the uncoupling of bone formation and resorption that is ultimately responsible for bone loss that occurs in post-menopausal osteoporosis. Any agent that could reverse this inhibition would "re-couple" bone formation and resorption and thus provide a novel therapeutic approach for treatment of post-menopausal osteoporosis and other bone disorders that are characterized by impaired bone formation. Osteoarthritis (OA) is also characterized by a cytokine-driven increase in matrix turnover in which localized inhibition of anabolic processes results in the development of focal degenerative lesions. We have used an in vitro OA model to identify two small molecule kinase inhibitors, from over 100 that were screened, that completely reverse IL-1 or TNF inhibition of IGF-1 anabolic function. The primary target for these two inhibitors is the same;however, the fact that other inhibitors with the same specificity for that same target cannot restore the IGF-1 response indicates that a second novel target must be involved. One objective of this Phase I proposal is to determine whether the same subset of kinase inhibitors that are effective in the in vitro OA model will prevent the TNF-inhibition of osteoblast differentiation and/or restore the impaired osteogenic potential of bone marrow progenitors derived from ovariectomized mice. Secondly, a chemistry effort will be initiated to generate proprietary drug candidates by screening a panel of compounds selected for their structural similarity to our active inhibitors. PUBLIC HEALTH RELEVANCE: Osteoporosis affects an estimated 10 million Americans over the age of 50 and is responsible for more than 1.5 million fractures annually. We propose to develop a novel therapy for osteoporosis that will stimulate new bone formation.